Resistance against cell death initiated by the tumor suppressor p53 is an important element in the development of leukemia and lymphoma. Normally, p53 can lead to cell death via induction of the proapoptotic Bcl-2 family member Puma, yet this death pathway is often suppressed in leukemia. One mechanism by which leukemic cells may inhibit Puma induction is through the enhanced glucose uptake and glycolysis that is characteristic of these cells. We have seen that increased glucose metabolism characteristic of cancer cells is sufficient to inhibit Puma induction upon growth factor withdrawal by suppressing p53 transcriptional activity. Given that increased glycolysis inhibits p53-dependent Puma induction, we hypothesize that the increased glucose metabolism of leukemic cells may regulate p53 activity and thereby suppress p53's ability to induce cell death. To test this hypothesis, we propose: (1) To investigate how elevated glucose metabolism might alter p53 signaling. Normal and glycolytic cells will be examined for differences in the transcriptional regulation of p53 target genes. p53 modifications and p53 protein interactions will also be examined for changes that may account for the decreased p53 activity seen in glycolytic cells. (2) To utilize a leukemogenesis assay to test the hypothesis that increased glucose metabolism and altered p53 signaling cooperate to prevent cell death and promote the development of leukemia. Using an established model system, we will determine whether increased glucose metabolism synergizes with the loss of p53 signaling to promote increased cell survival and increased incidence and/or decreased latency of tumorigenesis. Together these defined experiments will determine how a glycolytic phenotype characteristic of cancer cells influences p53-induced cell death and the development of leukemia. Further, findings from this proposal will form the basis for future experiments addressing the interplay between cell metabolism and cell death in cancer using both in vitro and in vivo leukemia development assays. PUBLIC HEALTH RELEVANCE: An estimated 116,000 new cases of leukemia and lymphoma are diagnosed yearly in the United States. With diseases that occur in both pediatric and adult populations, blood borne malignancies affect a broad spectrum of patients. By examining the role of metabolism in hematopoietic cell survival, these studies will address a novel aspect of cancer biology and illustrate possible new metabolic approaches to the treatment of leukemia and lymphoma.